Treating gastrointestinal diseases with modulators of retinoic acid

Abstract

T cells are programmed to target the gastrointestinal tract by activation with dendritic cells capable of producing and/or transporting retinoic acid. Methods for using the programmed dendritic cells and/or T and/or B cells to treat a variety of pathogens and infectious agents residing in the intestine are also disclosed. Similarly, inhibitors of retinoic acid synthesis by dendritic cells or other cells in the gut, and inhibitors of retinoic acid receptors in T and/or B cells or other cells in the intestinal mucosa, are disclosed for treating a variety of gastrointestinal autoimmune diseases such as inflammatory bowel disease and celiac disease.

1 . A method for conferring on dendritic cells which do not normally metabolize vitamin A into retinoic acid the ability to do so, said method comprising the steps of 
 selecting dendritic cells normally lacking the ability to metabolize vitamin A,    culturing said cells in the presence of retinoic acid (or retinoid agonists), and    evaluating said cells for (a) their ability to metabolize vitamin A and/or (b) their ability to induce gut homing and blocking skin homing receptors.    
   
   
       2 . A method for conferring on dendritic cells which do not normally metabolize vitamin A into retinoic acid the ability to do so, said method comprising the steps of 
 selecting dendritic cells normally lacking the ability to metabolize vitamin A,    transfecting said cells with the genes coding for enzymes required to synthesize retinoic acid, and    evaluating said cells for (a) their ability to metabolize vitamin A and/or (b) their ability to induce gut homing and blocking skin homing receptors.    
   
   
       3 . The method of  claim 2  wherein the enzyme is selected from the group consisting of RALDH-1. RALDH-2, RALDH-3, RALDH-4, ADH-I, ADH-II and ADH-III.  
   
   
       4 . A method for conferring on dendritic cells which do not normally transport, present or release retinoids the ability to do so, said method comprising the steps of 
 selecting dendritic cells normally lacking the ability to metabolize vitamin A,    culturing said cells in the presence of retinoic acid, and    evaluating said cells for their ability to induce gut homing and to blocking skin homing receptors.    
   
   
       5 . The method of  claim 4  wherein the retinoids are retinoic acid and/or retinoic acid receptor agonists.  
   
   
       6 . The method of  claim 1  wherein the dendritic cells are obtained from a source selected from the group consisting of non-lymphoid tissue, bone marrow, peripheral blood, cord blood monocytes, DC precursors, adult embryonic stem cells and the spleen.  
   
   
       7 . A pharmaceutical composition comprising the dendritic cells obtained by the methods of  claim 1  a pharmaceutically active drug substance, a pharmaceutically acceptable carrier, and an adjuvant.  
   
   
       8 . The composition of  claim 7  which is selected from the group consisting of oral formulations, subcutaneous formulations, intravenous formulations and intraperitoneal formulations.  
   
   
       9 . A method for programming T and/or B cells to target the gastrointestinal tract comprising activating the cells in the presence of dendritic cells capable of metabolizing vitamin A and/or transporting, presenting or releasing, or contacting the T or B cells with dendritic cells which are capable of metabolizing vitamin A.  
   
   
       10 . The method of  claim 9  wherein the T and/or B cells are selected from the group consisting of regulatory T cells, naïve and/or effector/memory T and/or B cells, plasmablasts and plasma cells.  
   
   
       11 . The method of  claim 9  wherein the T and/or B cells express the molecules α4β7 and CCR9.  
   
   
       12 . The method of  claim 9  wherein the expression of skin homing receptors in said T or B cells is suppressed.  
   
   
       13 . A pharmaceutical composition comprising the T and/or B cells of  claim 9 , a pharmaceutically active drug substance, a pharmaceutically acceptable carrier, and an adjuvant.  
   
   
       14 . The composition of  claim 13  which is selected from the group consisting of oral formulations, subcutaneous formulations, intravenous formulations and intraperitoneal formulations.  
   
   
       15 . A method for treating a subject having a pathogen or infectious agent residing in the gastrointestinal tract of said subject comprising administering to the patient the pharmaceutical composition of  claim 13  in an effective dosage amount.  
   
   
       16 . A method for treating a subject having a tumor residing in the gastrointestinal tract of said subject comprising administering to the subject the pharmaceutical composition of  claim 13  in an effective dosage amount.  
   
   
       17 . A method for treating an autoimmune disease or inflammatory condition of the gastrointestinal tract comprising administering to a subject an agent capable of inhibiting an enzyme selected from the group consisting of RALDH-1, RALDH-2, RALDH-3, RALDH-4, ADH-I, ADH-II and ADH-III, and/or administering to a subject an agent capable of blocking retinoic acid receptors  
   
   
       18 . The method of  claim 17  wherein the autoimmumne disease is selected from the group consisting of inflammatory bowel diseases and celiac disease.  
   
   
       19 . The method of  claim 17  which is used as an adjunct with another therapeutic treatment.  
   
   
       20 . A method for treating autoimmune or hypersensitivity skin diseases by immunizing a subject with dendritic cells capable of producing and/or transporting retinoic acid or retinoid agonists to block, suppress and/or reverse the acquisition of skin homing receptors on T and/or B cells.  
   
   
       21 . The method of  claim 20  wherein the disease is psoriasis or skin delayed hypersensitivity response.  
   
   
       22 . The method of  claim 9  wherein the programmed cells are regulatory T cells with intestinal-migratory potential for treating and/or preventing autoimmune or hypersensitivity diseases affecting the gastrointestinal mucosa, including inflammatory bowel diseases and celiac disease.  
   
   
       23 . An improved vaccine formulation for treating gastrointestinal disorders comprising 
 a vaccine formulation directed against one or more specific pathogens or infectious agents of the gastorintestinal tract, and    dendritic cells obtained by the methods of claims  1 ,  2  or  4 .    
   
   
       24 . The imrpoved vaccine of  claim 23  wherein the pahtogens or infectoius agents are selected form the group consisting of HIV, salmonella, rotavirus and poliovirus.  
   
   
       25 . The vacine formulation of  claim 23  which also includes adjuvants, excipients and carriers.  
   
   
       26 . A method of boosting a vaccine formulating by targetting the vaccine to the intestinal mucos comprising combining the vaccine ex vivo with dendritic cells obtained by the methods of  claim 1.